IL 10 MODULAT PROINFLAMMAT CYTOKINES INDUC BY BORRELIA LIPOPROTEINS: LYME DIS

$0P51FY2002RRNIH

Tulane University Of Louisiana, New Orleans LA

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Abstract

Borrelia burgdorferi lipoproteins are known to induce local and systemic production of the proinflammatory cytokines IL-6, IL-1( and TNF-( in macrophages. These cytokines are implicated in the pathogenesis of Lyme disease. We have reported that heat-killed B. burgdorferi spirochetes (Bb) and lipidated outer surface protein A (L-OspA) but not unlipidated OspA (U-OspA) are able to stimulate not only the production of inflammatory cytokines but also that of the anti-inflammatory cytokine IL-10 in peripheral blood mononuclear cells from uninfected humans and rhesus monkeys. Monocytes are the cells that transcribe both types of cytokines. We have now demonstrated in a kinetic study that in the monocytic cell line THP-1, stimulation with Bb, L-OspA and LPS but not U-OspA induces the production of IL-1(, IL-6, IL-10, IL-12 and TNF-(. TNF-( was detected at 1 hr, with peak levels observed at 2 hr, followed by a decline at 48 hr. IL-1( was detected at 2 hr; its level peaked at 24 hr and rema ined high throughout. Cells stimulated with L-OspA, Bb or LPS produced IL-6 after 8 hr with maximal levels seen at 48 hr; levels remained high up to 168 hr. IL-12 production kinetics mirrored that of IL-6. IL-10 was detected at 8 hr with peaked level occurring between 8 to 16 hr; its level remained stable between 24-72 hr followed by a gradual decline thereafter. Exogenously added recombinant IL-10 (rIL-10) to L-OspA or LPS cultures elicited 100% inhibition of IL-12 production using 0.1 ng/ml. The inhibitory effect of rIL-10 on IL-1(, IL-6 and TNF-( production was dose dependent. Conversely, the addition of anti-IL-10 enhanced only IL-6 and IL-12 production. These results show that IL-10 induced by B. burgdorferi lipoproteins downregulates proinflammatory responses similarly induced by lipoproteins. They further suggest that IL-10 induced by the spirochete may contribute to control inflammation in Lyme disease and that exogenous rIL-10 might be therapeutically useful. FUNDING CDC PUBLICATIONS None

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